The purine analogs with which the present invention is concerned has the following structural formula I and Ia. ##STR1## wherein R=C is 9-deazainosine (9-DINO) and
R=N is formycin B.
The synthesis of the above analogs and the disclosure of their antitumor and antiprotozoal activities are described in the following publications.
1. R. Klein, et al., Tetrahedron Letters, 21, 1013-1016, (1980).
2. Mee-ILL Lim, et al., Journal of Organic Chemistry, 48, 780-788, (1983).
3. J. Joseph Marr, et al., Antimicrobial Agents and Chemotherapy, 25, 292-295 (1984).
4. J. Joseph Marr, et al., Antimicrobial Agents and Chemotherapy, 27, 33-36, (1985).
5. J. Joseph Marr, et al., Antimicrobial Agents and Chemotherapy, 30, 1981-183, (1986).
The above publications numbered 1 and 2, namely Tetrahedron Letters and the Journal of Organic Chemistry, describe the synthesis of the purine analogs, of forumula I of the present invention and their use as antitumor agents.
J. Joseph Marr, et al., Antimicrobial Agents and Chemotherapy, 25, 292-295, (1984), describes the activities of six purine analogs, namely, 7-deazainosine, 9-deazainosine, allopurinol riboside, formycin B, 8-azainosine and 7-thia 7,9-dideazainosine against the three protozoan pathogens Leishmania donovani, Trypanosoma cruzi, and Trypanosoma gambiense.
The two latter pathogens include American as well as African trypanosomes. All these six analogs were active against the above three pathogens in tissue culture systems that is in vitro.
J. Joseph Marr, et al., Antimicrobial Agents and Chemotherapy, 27, 33-36, (1985), also describes six purine analogs, which are allopurionol, allopurinol ribonucleoside, thiopurinol, thiopurinol ribonucleoside, formycin B and 9-deazainosine and their activity against Trypanosoma brucei gambiense, and Trypanosoma brucei rhodesiense in cell cultures that is in vitro and in vivo against bloodstream forms grown in a bone marrow tissue culture system. The two carbon-nucleosides, namely, formycin B and 9-deazainosine were found to be active at very low concentrations with formycin B somewhat more efficacious than 9-deazainosine in the bone marrow tissue culture system.
Finally, the last publication, J. Joseph Marr et al., Antimicrobial Agents and Chemotherapy, 30, 181-183, (1986), describes three analogs of inosine, formycin B, allopurinol ribonucleoside, and 9-deazainosine and their activities against Pneumocystis Carinii in tissue culture system. The two analogs formycin B and 9-deazainosine were active in this tissue culture system. The organism Pneumocystis Carinii causes pneumonia in humans.
The present invention can be distinguished from the above prior art in that it is directed to a use which is unexpected and which can be distinguished from its application in the above-described tissue culture system. Usefulness in any of the above systems would not suggest or in any way make obvious the use of the purine analogs of formula I and Ia of the present invention in Trypanosoma brucei brucei infections, which causes African human and veterinary trypanosomiases that is sleeping sickness.
Treatment of African trypanosomiasis has a long history dating back to 1905 with the discovery of phenyl-arsenical atoxyl. Since that time, the control of human African sleeping sickness has rested on two additional arsenicals, one naphthylamine sulfonic acid and one diamidine, all discovered before 1950. These compounds have severe toxicity problems and therefore, present safety problems. A list of compounds and their combinations which are currently used for the treatment of this disease is found in Chapter 5, pages 129-136, entitled "Protozoan Infections of Man African Trypanosomiasis" in Chemotherapy of Parasitic Diseass, Editors William C. Campbell and Robert S. Rew, Publisher Plenum Press, 1986.
However because of the toxicities of these compounds and their combinations, no safe effective treatment for this disease in man is presently available.
In summary, there exists nothing in the prior art that would teach or suggest that purine analogs of formula I and Ia of the present invention and their pharmaceutically acceptable salts would be useful for treating African human and veterinary trypanosomiases. The purine analogs and their pharmaceutically acceptable salts of the present invention can be surprisingly used to treat this disease with little or no toxicity to the human being or an animal.